Effect of Food on the Pharmacokinetics of the Oral Docetaxel Tablet Formulation ModraDoc006 Combined with Ritonavir (ModraDoc006/r) in Patients with Advanced Solid Tumours

Marit A C Vermunt, Vincent A de Weger, Julie M Janssen, Marta I Lopez-Yurda, Marianne Keessen, Bas Thijssen, Hilde Rosing, Alwin D R Huitema, Jos H Beijnen, Serena Marchetti, Marit A C Vermunt, Vincent A de Weger, Julie M Janssen, Marta I Lopez-Yurda, Marianne Keessen, Bas Thijssen, Hilde Rosing, Alwin D R Huitema, Jos H Beijnen, Serena Marchetti

Abstract

Introduction: ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r.

Objectives: This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir.

Methods: Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03.

Results: In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration-time curve (AUC)0-48, AUC0-inf and maximum concentration (Cmax) were 1.11 (90% confidence interval [CI] 0.93-1.33), 1.19 (90% CI 1.00-1.41) and 1.07 (90% CI 0.81-1.42) in fed versus fasted conditions, respectively. For the ritonavir Cmax, the GMR was 0.79 (90% CI 0.69-0.90), whereas the AUC0-48 and AUC0-inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity.

Conclusions: The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir Cmax. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel. CLINICALTRIALS.

Gov identifier: NCT03147378, date of registration: May 10 2017.

Conflict of interest statement

J.H. Beijnen is a (part-time) employee, patent holder and stockholder of Modra Pharmaceuticals BV. Marianne Keessen is a full-time employee of Modra Pharmaceuticals BV. Marit A.C. Vermunt, Vincent A. de Weger, Julie M. Janssen, Marta I. Lopez-Yurda, Bas Thijssen, Hilde Rosing, and Alwin D.R. Huitema Serena Marchetti have no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1.
Fig. 1.
Study design and patients. In total, 18 patients were screened and randomized (1:1) to arm A or B. Each patient received ModraDoc006 30 mg in combination with ritonavir 100 mg with or without a high-fat meal in week 1 or 2, according to the randomization arm. In arm A, nine patients were randomized. One patient did not start with ModraDoc006/r because of symptomatic brain metastases diagnosed on the starting day and was excluded from safety and pharmacokinetic evaluation. A second patient in arm A received only one administration of ModraDoc006/r (in fasted condition) and discontinued in week 2 because of rapid clinical deterioration due to disease progression and development of a pneumosepsis; neither event was considered related to study medication. This patient was evaluable for safety but not for the pharmacokinetic food-interaction evaluation. In arm B, all nine randomized patients completed the food-effect study and were evaluable for safety and pharmacokinetic analysis. PK pharmacokinetics, Wk treatment week
Fig. 2
Fig. 2
Mean plasma concentration versus time curves of docetaxel after administration of ModraDoc006/r in fasted and fed conditions. SEM standard error of the mean
Fig. 3
Fig. 3
Mean plasma concentration versus time curves of ritonavir after administration of ModraDoc006/r in fasted and fed conditions. SEM standard error of the mean

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